A wide array of blinding and visually impairing disorders is caused by degeneration of the photoreceptors of the retina. The retina is a complex structure comprising several layers of neuronal cell types, as well as the Müller glia, and the adjacent RPE. Photoreceptors are structurally polarized neurons with several unique features. At one pole of the neuron is the chemical synapse; at the other end is the outer segment (OS), the most highly specialized region of the photoreceptor cell. Vision begins at the level of the photoreceptor OS.
Functional and anatomical integrity of the OS is essential for proper light detection and optimal vision. As seen by electron microscopy, the OS comprises an array of up to 1,000 flattened stacked membranous saccules or “discs” in perfect register, surrounded by a plasma membrane (2, 3). The membranous discs are continuously renewed at the proximal end of the OS, and the distal ends of the OS are shed and phagocytized daily by the adjacent layer of cells known as the retinal pigmented epithelium (RPE) (1). Several of the steps that lead to formation and organization of OS have been elucidated; however the chain of events that regulates OS assembly remains incompletely characterized.
The health and survival of the photoreceptors are heavily dependent on the integrity of other surrounding cell types of the retina, including RPE cells and the Müller cells. The importance of an intact and fully functional RPE on photoreceptor development and survival has long been recognized. In addition to its role in phagocytosis (1), the RPE is necessary to support photoreceptor OS development and differentiation (4). RPE-secreted proteins including pigment epithelium-derived factor (PEDF) promote photoreceptor differentiation and survival (5-9). At present, the nature of the RPE-produced factors that are necessary for morphogenesis of the photoreceptors is beginning to be elucidated.
The Müller cells of the retina are also recognized to play important roles in photoreceptor development and survival. Müller cells are coupled embryologically, physically, and metabolically to photoreceptors (10). It has been proposed that Müller cells provide trophic support to promote photoreceptor survival (10-12) and may regulate synaptogenesis (13, 14) and neuronal processing (15) through bidirectional communication (16). During development, Müller cells, photoreceptors and a subset of inner retinal neurons originate from a single retinal progenitor and arrange themselves in a columnar fashion (10, 17) in which Müller cells surround photoreceptors from the synaptic terminals to the inner segments (18), where the two cells are connected via the adherens junctions that comprise the outer limiting membrane of the retina (reviewed in (19) and (20)). In addition, Müller cells express voltage-gated ion channels, neurotransmitter receptors and various uptake carrier systems which enable them to modulate the activity of retinal neurons (21). Targeted disruption of Müller cell metabolism with α-aminoadipic acid results in disorganization of OS both in RPE-supported retinas and in RPE-deprived retinas exposed to IPTG. Thus, it is believed that Müller cells interact with photoreceptors through mechanisms that may regulate, at least in part, the assembly of OS membranes (22, 23).
Recently there has been recognition that specific glycans play important physiological roles in non-retinal tissues, e.g., functions related to innate immunity or parasitic adhesion. Recently, receptors specific for unique glycans have been cloned and partially characterized in several tissues (24-30). In the liver, it has been shown that the affinity of the receptors for glycan ligands is markedly enhanced for multivalent ligands, suggesting that the clustering of terminal sugar residues promotes strong receptor-ligand interactions (24, 25, 27, 28, 31, 32). Recent publications have documented the discovery of Dectin-1, a novel β-glucan receptor, and its role in modulating the immune system response by inducing leukocyte activation and the production of mediators of inflammation (26, 29, 30). Additionally, mannose-binding receptors have been cloned and characterized in Acathamoeba, and shown to play a critical role in adhesion of the parasite to host cells (33).
There is general recognition that carbohydrates play a role in maintaining the integrity of the photoreceptor OS. It has been previously recognized that carbohydrates and their lectin receptors play an important physiological role in the retina. Carbohydrates have both a metabolic and a non-metabolic role in retinal physiology. The metabolic role of carbohydrates in the retina has been previously studied (34, 35). In addition to having metabolic functions in the retina, carbohydrates also play fundamental non-metabolic roles. For example, tunicamycin, an antibiotic that prevents the formation of N-linked oligosaccharides via the lipid intermediate pathway during protein glycosylation significantly alters membrane morphogenesis in adult Xenopus retinas, suggesting that the lack of sugar moieties on glycoproteins within the retina may be responsible for the misassembly of OS membranes (36-38). If post-translational trimming of oligosaccharides is inhibited with castanospermine, however, nascent disc morphology is identical to control conditions, suggesting that post-translational removal of oligosaccharides is not essential for normal disc morphogenesis (39).
Several sub-types of lectins, including lactose-binding lectins, have been localized to the retina (40-43). In addition, lectin-binding sites of the outer retina have been described (44-47). For example, a 16 kD galectin has been suggested to play a modulating role in the interactions between the RPE and the retina (48). Moreover, its presence throughout Müller cells suggests a role in metabolic processing between Müller cells and other retinal cells (48). Additionally, specific expression of galectin at the outer limiting membrane (OLM) underscores its probable role in mediating cell-cell interactions between Müller cells and photoreceptors. Involvement of galectin-1 in regulating the adhesion of photoreceptors and the outer plexiform layer has also been proposed (49).
The presence and uptake of several glycans of the A3 family has been demonstrated in the retina. In the rat, immunoreactivity for fetuin has been reported to be present during development in cells of the ganglion cell layer and in a small population of the cells in the neuroblastic layer (56). A wider distribution of retina-derived fetuin, in the RPE as well as in ganglion cells, photoreceptor inner segments, the outer plexiform layer and optic nerve processes has also been reported (57). Fluoresceinated alpha-fetoprotein is taken up exclusively by maturing neurons of the chick retina, rather than undifferentiated precursors or fully differentiated neurons, indicating that alpha-fetoprotein may play a role in retinal maturation. Together these studies demonstrate that members of the A3 family of glycans are present in the retina, and that the ligand-receptor complex is internalized in a manner that is similar to that demonstrated for the asialoglycoprotein receptors of the liver (58).
Despite these advances, the nature of the molecular signals that regulate photoreceptor OS assembly are not well understood at present. There is a clear need for better understanding of the mechanisms by which photoreceptor OS assembly occurs, is maintained, and breaks down in retinal diseases and disorders. It would be particularly desirable to identify and characterize glycan-binding proteins that mediate these essential processes in the retina, and to develop new therapeutic approaches and agents based thereon.